This invention relates to a finely ground powder of N-(1-((2,4-diamino-6-pteridinyl)methyl)-3,4-dihydro-2H-1,4-benzothiazine-7-carbonyl)L-xcex1-aminoadipic acid (hereinafter also referred to as MX-68), a method for treating a bulk MX-68 powder, solid oral preparations containing this finely ground powder as the active ingredient, and a method for producing the same.
Bulk powder of MX-68, studies on which are in progress as a novel antirheumatic, can be separated depending on difference in crystallization solvents into an amorphous fine powder and a crystalline bulk powder involving coarse particles, having a wide particle size distribution and showing slight orientation. The amorphous bulk powder of MX-68, which is obtained mainly from organic solvent solutions, shows an extremely high dissolution speed and a high degree of mixing with additives because of being a fine powder. However, it suffers from a disadvantage of having poor stability. On the other hand, the crystalline bulk powder of MX-68, which is obtained mainly from aqueous solutions, is superior in stability to the amorphous bulk powder. However, there has been discovered a problem that this crystalline bulk powder cannot ensure high content uniformity in preparations due to the low solubility and non-uniform particle size thereof. Accordingly, it has been required to provide a means of solving the problems of the solubility and content uniformity while sustaining the high stability of the bulk MX-68 powder. As a means of improving the solubility of the bulk powder and the content uniformity of preparations, attempts have been made to enlarge the surface area of the bulk powder by reducing the particle diameter so as to elevate the dissolution speed. Thus, there have been employed mechanical grinding methods by taking advantage of friction between the bulk powder and a pulverizer such as a ball mill or a hammer mill. It is also known that the dissolution speed can be elevated by making the crystalline bulk powder amorphous. In the case of the crystalline bulk powder of MX-68, however, the stability is lowered with a decrease in the crystallinity. Therefore, it has been required to develop a grinding method whereby the crystalline bulk powder can be finely ground while sustaining its crystallinity.
The present inventors have conducted intensive studies to solve the above-described problems. As a result, they have successfully found that a finely ground powder having an average particle diameter of 5 to 25 xcexcm and sustaining the crystallinity can be obtained by finely grinding a crystalline bulk powder of MX-68 by an impact grinding method or a jet mill grinding method and preparations having improved dissolution properties and content uniformity can be obtained by using the finely ground powder thus obtained. The present invention has been completed based on these findings.
Accordingly, the present invention provides a finely ground powder of MX-68 which has an average particle diameter of 5 to 25 xcexcm and sustains its crystallinity even after grinding.
The present invention further provides solid oral preparations containing as the active ingredient a finely ground powder of MX-68 which has an average particle diameter of 5 to 25 xcexcm and sustains its crystallinity even after grinding.
The present invention further provides a method for treating a bulk powder of MX-68 which comprises grinding a crystalline bulk powder of MX-68 to give a finely ground powder of MX-68 having an average particle diameter of 5 to 25 xcexcm and sustaining its crystallinity even after grinding.
The present invention furthermore provides a method for producing solid oral preparations containing as the active ingredient a finely ground powder of MX-68 which involves the step of grinding a crystalline bulk powder of MX-68 by using an impact grinding method or a jet mill grinding method.
According to the present invention, a crystalline bulk powder of MX-68 is treated by using an impact grinding method or a jet mill grinding method so that solid oral preparations showing rapid release of the active ingredient and ensuring high content uniformity can be obtained without adversely affecting the stability. In the present invention, the crystalline bulk powder of N-(1-((2,4-diamino-6-pteridinyl)methyl)-3,4-dihydro-2H-1,4-benzothiazine-7-carbonyl)L-xcex1-aminoadipic acid can be obtained in accordance with the method as will be described in Example 1 hereinafter (i.e., the method described in Japanese Laid-Open Patent Publication No. 6-239863(A)) which comprises adjusting an alkaline aqueous solution of MX-68 to its isoelectric point and crystallizing. Alternatively, this crystalline bulk powder can be obtained by adjusting an acidic aqueous solution of MX-68 to its isoelectric point followed by crystallization. Moreover, crystalline powders obtained by other methods are also usable as the crystalline bulk powder of MX-68 in the present invention.